Department of Translational and Precision Medicine "Sapienza" University of Rome Rome Italy.
Department of Experimental Medicine "Sapienza" University of Rome Rome Italy.
J Am Heart Assoc. 2021 May 4;10(9):e018932. doi: 10.1161/JAHA.120.018932. Epub 2021 Apr 23.
Background Familial hypercholesterolemia (FH) may arise from deleterious monogenic variants in FH-causing genes as well as from a polygenic cause. We evaluated the relationships between monogenic FH and polygenic hypercholesterolemia in influencing the long-term response to therapy and the risk of atherosclerosis. Methods and Results A cohort of 370 patients with clinically diagnosed FH were screened for monogenic mutations and a low-density lipoprotein-rising genetic risk score >0.69 to identify polygenic cause. Medical records were reviewed to estimate the response to lipid-lowering therapies and the occurrence of major atherosclerotic cardiovascular events during a median follow-up of 31.0 months. A subgroup of patients (n=119) also underwent coronary computed tomographic angiography for the evaluation of coronary artery calcium score and severity of coronary stenosis as compared with 135 controls. Two hundred nine (56.5%) patients with hypercholesterolemia were classified as monogenic (FH/M+), 89 (24.1%) as polygenic, and 72 (19.5%) genetically undefined (FH/M-). The response to lipid-lowering therapy was poorest in monogenic, whereas it was comparable in patients with polygenic hypercholesterolemia and genetically undetermined. Mean coronary artery calcium score and the prevalence of coronary artery calcium >100 units were significantly higher in FH/M+ as compared with both FH/M- and controls. Finally, after adjustments for confounders, we observed a 5-fold higher risk of incident major atherosclerotic cardiovascular events in FH/M+ (hazard ratio, 4.8; 95% CI, 1.06-21.36; =0.041). Conclusions Monogenic cause of FH is associated with lower response to conventional cholesterol-lowering therapies as well as with increased burden of coronary atherosclerosis and risk of atherosclerotic-related events. Genetic testing for hypercholesterolemia is helpful in providing important prognostic information.
家族性高胆固醇血症（FH）可能由 FH 致病基因的有害单基因变异以及多基因原因引起。我们评估了单基因 FH 和多基因高胆固醇血症对治疗反应的长期影响和动脉粥样硬化风险的关系。
对 370 例临床诊断为 FH 的患者进行单基因突变筛查和低密度脂蛋白升高的遗传风险评分>0.69，以确定多基因病因。回顾病历以评估降脂治疗的反应，并在中位数为 31.0 个月的随访期间发生主要动脉粥样硬化性心血管事件。对 119 例患者进行了冠状动脉计算机断层扫描血管造影术，以评估冠状动脉钙评分和冠状动脉狭窄程度，并与 135 例对照进行比较。209 例（56.5%）高胆固醇血症患者被归类为单基因（FH/M+），89 例（24.1%）为多基因，72 例（19.5%）遗传不确定（FH/M-）。单基因 FH 患者的降脂治疗反应最差，而多基因高胆固醇血症患者和遗传不确定的患者的反应相当。与 FH/M-和对照组相比，FH/M+的平均冠状动脉钙评分和冠状动脉钙>100 单位的患病率明显更高。最后，在调整混杂因素后，我们观察到 FH/M+发生主要动脉粥样硬化性心血管事件的风险增加 5 倍（危险比，4.8；95%CI，1.06-21.36；=0.041）。
FH 的单基因病因与常规降脂治疗反应降低以及冠状动脉粥样硬化负担增加和动脉粥样硬化相关事件风险增加相关。高胆固醇血症的基因检测有助于提供重要的预后信息。
